Pharmaceutical microbubble technology uses microbubbles smaller than red blood cells as ultrasound contrast agents and for targeted drug and gene delivery. Microbubbles are composed of an inner gas core surrounded by a shell, with an outer aqueous layer. They can be produced using cross-linking, atomization, or sonication methods. Microbubbles are characterized based on size, shell thickness, concentration, and gas content. Applications include use as diagnostic aids with ultrasound imaging, for gene delivery by encapsulating genes and releasing them at target sites using ultrasound, and in drug delivery by loading drugs onto the microbubble shell. Several commercial microbubble formulations are approved for cardiac, hepatic, and cancer applications.

1. Pharmaceutical Microbubble Technology
Matoshri institute of pharmacy Dhanore , yeola dist – nashik
Sonawane harsha , Pawar ashwini Guided by – Ms Wagh G.M.
Properties:
I]Functional Properties:
• Injectability: They should be injectable. When injected
into the body they do not produce any immune response.
• Ultrasound Scattering Efficiency: They are used
combination with ultrasound and have ultrasound
scattering efficiency.
• Biocompatibility: They should be Biocompatible as they
are interacting with the vital organs of the body.
• They are metabolically inert.
• It carries encapsulated or attached gene to its target
without getting digested by the various enzymes. This
Feature will significantly useful in gene delivery.
II]Structural Properties:
• Diameter: should be between the ranges of 1-10 μm.
• Density & compressibility: In Body, They are act as
contrast agents because their density & compressibility
difference between themselves & the surrounding body
tissues to create acoustic impedance & to scatter
ultrasound at a much higher intensity than the body
tissues.
• Uniformity of shell thickness: They have uniform shell
thickness.
Components: Microbubbles comprise of
basically 3 layers; inner, middle and outer most layer. They
are as following:
1) Innermost Gas Layer
2) Shell Material Enclosing the Gas Layer
3) Outermost Liquid or Aqueous Layer
Fig.: Component Of Microbubble
1)Inner most layer:
• Gas layer which is single or a combination of gases.
• Combination gases are used to cause differentials in
partial pressure & to generate gas osmotic pressures
which stabilize the bubbles.
• Primary Modifier Gas known as First gas. Eg. Air and
Nitrogen.
• Second gas is a Gas Osmotic Agent, it is preferably a gas
that is less permeable through the bubble surface than
the modifier gas. Eg. per fluorocarbons or sulfur
hexafluoride.
2)Shell Material:
• It covers the gas phase. It plays a major role in the
mechanical properties of microbubble.
• The shell also acts a region for encapsulation of drug molecules also ligands can be attached to
the shell membrane so as to achieve targeting of these microbubbles to the various organs or
tissues.
• Materials are used in a shell material:
- Proteins like albumin,
-Surfactants like Span 40 & tween 40,
-Phospholipids like phosphotidyl- choline, phosphotidyl-ethanolamine,
-Biodegradable polymers like polyvinyl alcohol, polycaprolactone,
3)Aqueous or Liquid Phase:
• The external, continuous liquid phase in which the bubble resides typically made up of surfactant
or foaming agent.
• Surfactants suitable for use include any compound or composition that aids in the formation &
maintenance of the bubble membrane by forming a layer at the interphase.
• The foaming agent or surfactant may be made up of a single component or any combination of
compounds, such as in the case of co surfactants. eg., copolymers of polyoxy- propylene,
polyoxyethylene, sugar esters, fatty alcohols, aliphatic amine oxides, hyaluronic acid esters &
their salts, dodecyl poly(ethyleneoxy)ethanol, etc.
4) Other Components: The other components that may be incorporated in the formulation to fine
tune the microbubble suspensions for maximum shelf life, contrast effectiveness, sterility,
isotonicity & biocompatibility may govern the use of such conventional additives to injectable
compositions, include;
viscosity modulators, air solubility modifiers, osmotic agents, stabilizers, buffers, chelators, Salts &
sugars.
Method of Preparation:
The various methods that can be used for the preparation of microbubbles are as follows;
1)Cross Linking Polymerization
2)Atomization & Reconstitution
3)Sonication
1)Cross Linking Polymerization: In this a polymeric solution is vigorously stirred, which results in
the formation of a fine foam of the polymer. The polymer is then cross linked, after cross linking
microbubbles float on the surface of the mixture. Floating microbubbles are separated & extensively
dialyzed against Milli Q water. The polymer acts as a colloidal stabilizer as well as a bubble coating
agent. eg., 2% aqueous solution of telechelic PVA is vigorously stirred at room temperature for 3 hrs
at a pH of 2.5 by an Ultra Turrax T-25 at 8000 rpm equipped with a Teflon coated tip, fine foam of
PVA is formed. The PVA is then cross linked at room temperature and at 5̇˚C by adding HCl or
H2SO4 as a catalyst, the cross linking reaction is stopped by neutralization of the mixture and
microbubbles are then separated.
• 2)Atomization & Reconstitution: A spray dried surfactant solution is formulated by atomizing a
surfactant solution into a heated gas which results in formation of porous spheres of the
surfactant solution with the primary modifier gas enclosed in it.
• These porous spheres are then packaged into a vial, the headspace of the vial is then filled with
the second gas or gas osmotic agent.
• The vial is then sealed, at the time of use it is reconstituted with a sterile saline solution.
• Upon reconstitution the primary modifier gas diffuses out & the secondary gas diffuses in,
resulting in size reduction. The microbubbles so formed remain suspended in the saline solution
& are then administered to the patient.
• 3)Sonication:
• Sonication is preferred for formation of microbubbles.
• A vial containing a surfactant solution & gas can be sonicated through a thin membrane. Due to
Sonication microbubble forms.
• Sonication can be done by contacting or even depressing the membrane with an ultrasonic probe
or with a focused ultrasound “beam”.
• Once sonication is accomplished, the microbubble solution can be withdrawn from the vial &
delivered.
Characterization:
A. Diameter & Size Distribution: It can be determined by
Laser light Scattering, Scanning Electron
Microscopy(SEM) and Transmission Electron
Microscopy(TEM).
B. Shell Thickness: It is determined by coating the shell
with a fluorescent dye like Red Nile and then determined
by Fluorescent Microscopy against a dark background.
C. Microbubble Concentration: It is determined by counting
the no. of microbubbles per ml by using the Coulter
Counter technique.
D. Air Content by densitometry: The content of air
encapsulated within the microbubbles in the suspension
samples is measured by oscillation U-tube densitometry
with a DMA-58.
• The instrument is calibrated with air and purified water
prior to use.
• The density of the suspension is measured before and
after elimination of encapsulated air.
• The complete removal of encapsulated air is achieved by
5 min high powered sonication in a sonicator.
• The air content is calculated as, Cair = ρ1 –ρ2/ρ2 *100
Where, Cair is air content (%v/v);
ρ1 (g/ml) density before elimination of encapsulated
air;
ρ2 (g/ml) density after elimination of encapsulated
air.
Applications:
A] Diagnostic Aids:
B]Gene Delivery:
C]In Drug Delivery:
Marketed Formulations:
What is Microbubble?
• These are small spherical type of bubble which consists of a gas; they are separated from each other, so they do not agglomerates.
• They have an average size less than that of RBC’s i.e., (usually 1-100 micrometers) they are capable of penetrating even into the smallest blood capillaries & releasing
drugs or genes, incorporated on their surface, under the action of ultrasound.
• They have unique ability respond to ultrasound which makes them useful agents for contrast ultrasound imaging, molecular imaging, and targeted drug and gene
delivery.
Bra
nd
Na
me
Producer Gas
Used
Stabilisation Approved
Applicatio
ns
Sonaz
oid TM
GE
Healthcar
e
Perfluroc
arbon
Hydrogenate
d Egg
phosphatidyl
serine
Abdominal
Injury
Optiso
n TM
GE
Healthcar
e
Perfluroc
arbon
Albumin Cardiac
disease
Sono
Vue
TM
Bracco Sulphur
hexafluor
ide
Phospholipid Cardiac,
Hepatic,
Breast
Cancer
Defi
nity
TM
Lantheus
Medical
Imaging
Octafluro
propane
Phospholipid Cardiac,
Abdomen